Early antigen-specific B cell responses as markers of oxycodone vaccine efficacy

早期抗原特异性 B 细胞反应作为羟考酮疫苗功效的标志

• 批准号: 8484815
• 负责人: Marco Pravetoni
• 金额: $ 14.61万
• 依托单位: HENNEPIN HEALTHCARE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8484815
• 关键词: Antibodies; Antibody Formation; Antigen Targeting; Antigens; B cell repertoire; B-Cell Activation; B-Lymphocytes; Behavioral; Biological Assay; Biopsy; Brain; Carrier Proteins; Clinic; Clinical; Conjugate Vaccines; Dependence; Detection; Drug Addiction; Drug Formulations; Drug Kinetics; Flow Cytometry; Haptens; Health; Immune response; Immunization; Immunotherapy; Individual; Keyhole Limpet Hemocyanin; Marker Vaccines; Measures; Memory B-Lymphocyte; Methods; Mus; Oxycodone; Oxymorphone; Patients; Pharmaceutical Preparations; Pharmacotherapy; Positioning Attribute; Production; Proteins; Rattus; Reporting; Research; Rodent; Serum; Spleen; Structure of germinal center of lymph node; Testing; Time; Translations; Vaccination; Vaccine Antigen; Vaccine Design; Vaccines; addiction; base; clinically significant; drug of abuse; immunogenicity; improved; novel vaccines; pre-clinical; preclinical study; prescription drug abuse; prescription opioid; prescription opioid abuse; response; screening; vaccine development; vaccine efficacy; vaccine evaluation

DESCRIPTION (provided by applicant): Drug addiction vaccines show encouraging efficacy in pre-clinical studies, yet translation to the clinic has been slowed by the variability of serum antibody concentrations reported in immunized subjects. Establishing early markers of vaccine immunogenicity would help predict efficacy, accelerate screening of vaccine designs, and individualize vaccine design selection in clinical settings. The overall hypothesis of this study i that clinically significant responses to drug addiction vaccines (drug hapten-protein conjugate) can be predicted from the number of hapten-specific B cells in naive (unimmunized) and immunized subjects. Specifically oxycodone (OXY)-specific B cells will be compared between different OXY vaccines and will correlate with OXY-specific serum antibodies and OXY distribution before and after immunization with OXY vaccines in rodents. A recently developed strategy detects rare antigen-specific B cells in naive and immunized subjects. Antigen-specific B cells are selected from the total B cell repertoire present in an unimmunized or immunized host by a fluorescent antigen-based enrichment method and then characterized by flow cytometry. This method can be adapted to drug conjugate vaccines by conjugating drug haptens to a fluorescent carrier protein used to detect hapten-specific B cells. Our lab has developed two OXY vaccines showing a range of effects in reducing brain distribution and behavioral effects of OXY, one of the most commonly abused prescription opioids. These vaccines will be used to test if OXY-specific B cells can be used to explain variability between structurally different vaccines and individual variability between subjects after immunization. We will test the hypotheses that: 1) the numbers of pre- and post-immunization OXY-specific B cells will be higher for the more efficient OXY vaccine in both mice and rats 2) the numbers of pre- and post- immunization OXY-specific B cells will correlate with OXY-specific serum antibody titers and with the effect of immunization on OXY distribution to the brain in rats. This will be tested by: aim 1A) characterizing the time course of OXY-specific B cell and OXY-specific antibody responses to two OXY vaccines in mice to determine B cell responses; aim 1B) assessing the same method in a second species (rats); aim 2A) correlating pre- immunization na¿ve OXY-specific B cells to OXY-specific antibody titers and their effects on OXY distribution to the brain in rats, and aim 2B) correlating early post- immunization activated OXY-specific B cells to OXY- specific serum antibody titers and their effects on OXY distribution to brain in rats PUBLIC HEALTH SIGNIFICANCE. Prescription drug abuse is the fastest-growing drug problem in the US, with oxycodone and oxymorphone among the most abused. Drug addiction vaccines offer a promising advantage to current pharmacotherapies to treat dependence. Early screening of immunogenicity will enable individualized treatment by matching the vaccine to patient and rapid treatment adjustment. This approach could be expanded to other drug-conjugate vaccines.

描述（由申请人提供）：药物成瘾疫苗在临床前研究中显示出令人鼓舞的疗效，但由于免疫受试者中报告的血清抗体浓度的变异性，导致转化为临床的速度减慢。建立疫苗免疫原性的早期标志物将有助于预测效力，加速疫苗设计的筛选，并在临床环境中个性化疫苗设计选择。本研究的总体假设是，对药物成瘾疫苗（药物半抗原-蛋白缀合物）的临床显著应答可以从初始（未免疫）和免疫受试者中的半抗原特异性B细胞的数量预测。具体地，将在不同的OXY疫苗之间比较羟考酮（OXY）特异性B细胞，并将其与啮齿动物中用OXY疫苗免疫之前和之后的OXY特异性血清抗体和OXY分布相关联。最近开发的策略检测罕见的抗原特异性B细胞在幼稚和免疫对象。抗原特异性B细胞通过基于荧光抗原的富集方法从存在于未免疫或免疫宿主中的总B细胞库中选择，然后通过流式细胞术表征。通过将药物半抗原与用于检测半抗原特异性B细胞的荧光载体蛋白缀合，该方法可适用于药物缀合物疫苗。我们的实验室已经开发了两种OXY疫苗，在减少OXY的大脑分布和行为影响方面显示出一系列效果，OXY是最常滥用的处方阿片类药物之一。这些疫苗将用于检测OXY特异性B细胞是否可用于解释结构不同疫苗之间的变异性以及免疫后受试者之间的个体变异性。我们将检验以下假设：1）对于更有效的OXY疫苗，小鼠和大鼠中免疫前和免疫后OXY特异性B细胞的数量将更高; 2）免疫前和免疫后OXY特异性B细胞的数量将与OXY特异性血清抗体滴度以及免疫对大鼠中OXY向脑分布的影响相关。这将通过以下方式进行测试：目的1A）表征小鼠中OXY特异性B细胞和OXY特异性抗体对两种OXY疫苗的应答的时间过程，以确定B细胞应答;目的1B）在第二物种（大鼠）中评估相同的方法;目的2A）将免疫前免疫应答与免疫后免疫应答相关联。用OXY特异性B细胞检测OXY特异性抗体滴度及其对大鼠脑内OXY分布的影响，和目的2B）将免疫后早期活化的OXY特异性B细胞与OXY特异性血清抗体滴度及其对大鼠脑中OXY分布的影响相关联。处方药滥用是美国增长最快的毒品问题，羟考酮和羟吗啡酮是滥用最严重的药物之一。药物成瘾疫苗提供了一个有前途的优势，目前的药物疗法来治疗依赖。免疫原性的早期筛查将通过使疫苗与患者匹配和快速治疗调整来实现个体化治疗。这种方法可以扩展到其他药物结合疫苗。

项目成果

Hapten-specific naïve B cells are biomarkers of vaccine efficacy against drugs of abuse.

半抗原特异性幼稚 B 细胞是针对滥用药物的疫苗功效的生物标志物。

• DOI: 10.1016/j.jim.2014.01.010
• 发表时间: 2014
• 期刊: Journal of immunological methods
• 影响因子: 2.2
• 作者: Taylor,JJ;Laudenbach,M;Tucker,AM;Jenkins,MK;Pravetoni,M
• 通讯作者: Pravetoni,M

The frequency of naive and early-activated hapten-specific B cell subsets dictates the efficacy of a therapeutic vaccine against prescription opioid abuse.

• DOI: 10.4049/jimmunol.1500385
• 发表时间: 2015-06-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Laudenbach M;Baruffaldi F;Vervacke JS;Distefano MD;Titcombe PJ;Mueller DL;Tubo NJ;Griffith TS;Pravetoni M
• 通讯作者: Pravetoni M